1,2-Dichloroethane → [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide

HRID 1366678Notes

Reaction equation

HRID 1366678 reaction equation
[F:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[CH3:17])=[N:4][C:5]([CH3:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH:18](O)([CH3:20])[CH3:19].CN1C[CH2:27][O:26]CC1.[OH:29][N:30]1[C:34]2N=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.C(Cl)CCl.CN([CH:46]=[O:47])C>>[CH:37]1([CH2:38][C@@H:33]([C:27]([NH:9][NH:8][C:7]2[C:2]([F:1])=[C:3]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[N:4]=[C:5]([CH3:10])[N:6]=2)=[O:26])[CH2:34][N:30]([OH:29])[CH:46]=[O:47])[CH2:36][CH2:20][CH2:18][CH2:19]1

Participants

7

Reactant 6

HCID 111,2-DichloroethaneHCID 3776IsopropanolHCID 6228DimethylformamideHCID 79724-MethylmorpholineHCID 181649HOAtHCID 66936366(3S)-4-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-3-methylmorpholine

Product 1

HCID 58000539[(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamideYield 80%

Procedure

To a solution of (3S)-4-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-3-methylmorpholine (0.2123 g, 0.880 mmol) in DMF (4 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid, N,N-diisopropylethylamine salt, isopropanol solvate (327.1 mg, 0.661 mmol), N-methylmorpholine (0.290 ml, 2.64 mmol), 1-hydroxy-7-azabenzotriazole (0.108 g, 0.794 mmol), and EDC (0.152 g, 0.793 mmol). The solution was stirred overnight, and then purified directly by Gilson RPLC. To a solution of the residue in MeOH (7 mL) was added 10% Pd/C (50% water, 88 mg). The mixture was hydrogenated under balloon pressure for 1 h, and then filtered through a PTFE membrane. The resulting solution was concentrated in vacuo, dissolved in EtOAc, and concentrated in vacuo. The solid was collected by vacuum filtration and washed with hexanes to give [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (0.2326 g, 80% yield) as a white solid. LCMS: (M+H)+: 439.2.

Workup

  1. custompurified directly by Gilson RPLC
  2. additionTo a solution of the residue in MeOH (7 mL) was added 10% Pd/C (50% water, 88 mg)
  3. waitThe mixture was hydrogenated under balloon pressure for 1 h
  4. filtrationfiltered through a PTFE membrane
  5. concentrationThe resulting solution was concentrated in vacuo
  6. dissolutiondissolved in EtOAc
  7. concentrationconcentrated in vacuo
  8. filtrationThe solid was collected by vacuum filtration
  9. washwashed with hexanes

Sources & evidence

ORD record
ord-ede382fb3b02453dbf7a0a24929cf59c
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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